Protein tyrosine kinases (PTKs) are a class of proteases capable of catalyzing the phosphorylation of the phenolic hydroxyl groups of tyrosine residues in various proteins and thus activating functions of functional proteins. Protein tyrosine kinases (PTKs) play very important roles in the intracellular signal transduction pathways, and regulate a series of biochemical processes, such as cell growth, differentiation and death. Abnormal expression of protein tyrosine kinases can cause disorder of cell proliferation regulation, and further result in tumorigenesis. In addition, abnormal expression of protein tyrosine kinases is also closely associated with invasion and metastasis of tumors, angiogenesis in tumors and chemotherapy resistance of tumors.
Tyrosine kinase inhibitors can be used as a competitive inhibitor of adenosine triphosphate (ATP) binding to tyrosine kinase, and can competitively bind to tyrosine kinases, block the activity of tyrosine kinase and inhibit cell proliferation. Several protein tyrosine kinase inhibitors have been successfully developed.
Imatinib mesylate, as a protein tyrosine kinase inhibitor, is the first molecular targeted agent. It competitively inhibits the binding sites of adenosine triphosphate (ATP) to thymidine kinase (TK) receptors such as KIT, and prevents phosphorylation of TK, thereby inhibiting the signal transduction. Imatinib can inhibit the KIT mutation associated with kinase activity and the wild type KIT, and has therapeutic effect on various types of cancers. Imatinib can inhibit Bcr-Abl tyrosine kinases at the cellular level in vivo and in vitro, and selectively inhibit proliferation and induce apoptosis in cells of Bcr-Abl positive cell lines as well as leukemic cells from patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and acute lymphoblastic leukemia. In addition, Imatinib can also inhibit receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, thereby inhibiting PDGF and stem cell factor-mediated cellular events. Clinically, Imatinib is mainly used in treatment of patients with chronic myeloid leukemia (CML) in accelerated phase, blast crisis or chronic phase after failure of α-interferon therapy, and patients with unresectable or metastatic malignant gastrointestinal stromal tumor (GIST). Also, Imatinib is used for treating CD 117-positive gastrointestinal stromal tumors (GIST).
Development and clinical use of Imatinib opens a new era of molecular targeted tumor therapy. Long-term use of Imatinib, however, may cause drug resistance, and lead to tumor recurrence. With wide clinical use of Imatinib, problem of drug resistance has become increasingly prominent. The acquired drug resistance was mainly due to Bcr-Abl point mutations, which render Imatinib unable to bind to Bcr-Abl. Also, it has been found that hundreds of Bcr-Abl point mutations are associated with imatinib resistance, of which 15 to 20% of imatinib-resistant patients have T315I mutation. Emergence of imatinib resistance arouses the research upsurge of a new generation of tyrosine kinase inhibitors.
AP24534 developed by Ariad Pharmaceuticals, Inc. (as shown in Formula A) well addresses this problem. Research shows that AP24534 is effective for CML patients having T315I mutation and resistant to second-generation TKIs, and is a multi-targeted kinase inhibitor against Bcr-Abl and SRC. AP24534 may act on the wild type cells and T315I-mutated cells, and inhibit Bcr-Abl and all mutants thereof including the T315I variants resistant to various therapeutic drugs, and is a broad spectrum inhibitor of Bcr-Abl.
